The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D. R. Lowy and D. M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a xe2x80x9cCAAXxe2x80x9d or xe2x80x9cCys-Aaa1-Aaa2-Xaaxe2x80x9d box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively. Such enzymes may be generally termed prenyl-protein transferases. (S. Clarke., Ann. Rev. Biochem. 61:355-386 (1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)). The Ras protein is one of several proteins that are known to undergo post-translational farnesylation. Other farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly (N. E. Kohl et al., Science, 260:1934-1937 (1993) and G. L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of ras-dependent tumors in nude mice (N. E. Kohl et al., Proc. Natl. Acad. Sci U.S.A., 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice (N. E. Kohl et al., Nature Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck and Co., Rahway, N.J.) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of poly-isoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.
Inhibitors of farnesyl-protein transferase (FPTase) have been described in two general classes. The first are analogs of farnesyl diphosphate (FPP), while the second class of inhibitors is related to the protein substrates (e.g., Ras) for the enzyme. The peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Pat. No. 5,141,851, University of Texas; N. E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound. However, the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.
It has recently been reported that farnesyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-112930).
It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitors of farnesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 A1). It has also been disclosed that certain compounds which incorporate a pyrrolidine moiety are inhibitors of FPTase (WO 97/37900, and U.S. Pat. Nos. 5,627,202 and 5,661,161).
It is, therefore, an object of this invention to develop compounds that will inhibit prenyl-protein transferase and thus, the post-translational isoprenylation of proteins. It is a further object of this invention to develop chemotherapeutic compositions containing the compounds of this invention and methods for producing the compounds of this invention.
The present invention comprises macrocyclic compounds which inhibit prenyl-protein transferases. Further contained in this invention are chemotherapeutic compositions containing these prenyl-protein transferase inhibitors and methods for their production.
The compounds of this invention are illustrated by the formula A: 
The compounds of this invention are useful in the inhibition of prenyl-protein transferase and the prenylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of a prenyl-protein transferase are illustrated by the formula A: 
wherein
X1 is (C(R1a)2)nA1(C(R1a)2)nA2;
X2 is (C(R1b)2)pA3(C(R1b)2)p;
X3 is (C(R1c)2)qA4(C(R1c)2)q;
R1a, R1b and R1c are independently selected from:
a) hydrogen;
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, R10Oxe2x80x94, R6aS(O)m, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, xe2x80x94C(O)NR6R7, R10C(O)NR10xe2x80x94, (R10)2NC(O) NR10xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, R10OC(O)xe2x80x94, or R10OC(O)NR10xe2x80x94; and
c) unsubstituted or substituted C1-C6 alkyl, wherein one or more of the substituents on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C 10cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, R10Oxe2x80x94, R6aS(O)m, R10C(O)NR10xe2x80x94, (R10)2NC(O)NR10xe2x80x94, R10C(O)xe2x80x94, xe2x80x94C(O)NR6R7, R10OC(O)xe2x80x94, xe2x80x94N(R10)2, R10OC(O)NR10xe2x80x94, and halo;
A1, A3 and A4 are independently selected from
a) a bond,
b) xe2x80x94C(xe2x95x90O)xe2x80x94,
c) xe2x80x94HCxe2x95x90CHxe2x80x94,
d) xe2x80x94Cxe2x95x90Cxe2x80x94,
e) O,
f) NR10,
g) NR10C(O),
h) C(O)NR10,
i) OC(O)NR10,
j) NR10C(O)O,
k) S(xe2x95x90O)m,
l) C(O)O, and
m) OC(O);
A2 is selected from
a) a bond,
b) xe2x80x94C(xe2x95x90O)xe2x80x94,
c) NR10C(O),
d) S(xe2x95x90O)m, and
e) OC(O);
R2 is independently selected from:
a) hydrogen,
b) CN,
c) NO2,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heterocycle, unsubstituted or substituted,
g) C1-C6 alkyl, unsubstituted or substituted,
h) OR,
i) N3,
j) R6aS(O)m,
k) C3-C10 cycloalkyl, unsubstituted or substituted,
l) C2-C6 alkenyl, unsubstituted or substituted,
m) C2-C6 alkynyl, unsubstituted or substituted,
n) (R10)2NC(O)NR10xe2x80x94,
o) R10C(O)xe2x80x94,
p) R10C(O)NR10xe2x80x94,
q) R10OC(O)xe2x80x94,
r) xe2x80x94N(R10)2,
s) R10OC(O)NR10xe2x80x94, and
t) xe2x80x94(C1-C6 alkyl)NR10C(O)R13;
R3 is independently selected from:
xe2x80x83H, CN, NO2, halo, unsubstituted or substituted C1-C6 alkyl, N3, oxido, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted aralkyl, unsubstituted or substituted heterocyclylalkyl, C1-C6 perfluoroalkyl, CF3Oxe2x80x94, CF3CH2xe2x80x94, unsubstituted or substituted C3-C10 cycloalkyl, OR10, NR6R7, OR6, xe2x80x94C(O)R10, xe2x80x94O(C1-C6 alkyl)OR10, S(O)mR6a, xe2x80x94C(O)NR6R7, xe2x80x94NHC(O)R10, xe2x80x94(C1-C6 alkyl)OR10, and xe2x80x94(C1-C6 alkyl)C(O)R10;
R4 and R5 are independently selected from:
xe2x80x83H, OR10, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, 
xe2x80x83wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-C6 alkyl,
b) (CH2)nOR6,
c) (CH2)nNR6R7,
d) halogen,
e) CN,
f) aryl or heteroaryl,
g) perfluoro-C1-C4 alkyl,
h) S(O)mR6a,
2) C3-C6cycloalkyl,
3) OR6,
4) S(O)mR6a, 
R4 and R5 are attached to the same C atom and are combined to form xe2x80x94(CH2)uxe2x80x94 wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, xe2x80x94NC(O)xe2x80x94, and xe2x80x94N(COR10)xe2x80x94;
and any of R4 and R5 are optionally attached to the same carbon atom;
R6, R7 and R7a are independently selected from:
xe2x80x83H, C1-C6 alkyl, C3-C6 cycloalkyl, heterocycle, aryl, aralkyl, aroyl, heteraroyl, arylsulfonyl, heteroarylsulfonyl, C1-C4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from:
a) C1-C6 alkoxy,
b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
c) halogen,
d) HO, 
g) xe2x80x94S(O)mR6a, or
h) N(R10)2; or
R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;
R6a is selected from
a) C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with one or more of the following:
1) C1-4 alkoxy,
2) aryl or heterocycle,
3) halogen,
4) HO, 
6) SO2R6a,
7) N(R10)2; and
b) C1-C6 alkyl, unsubstituted or substituted with one or more of the following:
1) xe2x80x94C(R10)2C1-4 alkoxy,
2) aryl or heterocycle,
3) xe2x80x94C(R10)2halogen,
4) xe2x80x94C(R10)2OH, 
6) xe2x80x94C(R10)2SO2R6a, and
7) xe2x80x94C(R10)2N(R10)2;
R8 is independently selected from
a) hydrogen,
b) unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C4perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, CN, R6aS(O)m, xe2x80x94C(O)NR6R7, R10C(O)NR10xe2x80x94, NO2, (R10)2NC(O)NR10xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, R10OC(O)NR10xe2x80x94, N3, or xe2x80x94N(R10)2 and
c) C1-C6 alkyl, unsubstituted or substituted by C1-C4 perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R6aS(O)xe2x80x94m, R10C(O)NR10xe2x80x94, CN, xe2x80x94C(O)NR6R7, (R10)2NC(O)NR10xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, and R10OC(O)NR10xe2x80x94;
R9 is independently selected from
1) H, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted aryl, and unsubstituted or substituted heterocycle, wherein the substituted group is substituted with one or more of:
a) C1-C6 alkyl, unsubstituted or substituted,
b) (CH2)nOR6,
c) (CH2)nNR6R7,
d) halogen,
e) CN,
f) aryl, unsubstituted or substituted,
g) heterocycle, unsubstituted or substituted,
h) perfluoro-C1-C4 alkyl,
i) S(O)mR6a,
j) N(R10)2,
k) NR10C(O)R11,
l) NR10C(O)R11N(R10)2,
2) C3-C6 cycloalkyl,
3) S(O)1-2R6a, 
8) xe2x80x94(C1-C6 alkyl)NR10C(O)R13;
R10 is independently selected from
a) hydrogen,
b) unsubstituted or substituted C1-C6 alkyl,
c) unsubstituted or substituted C3-C6 cycloalkyl,
d) 2,2,2-trifluoroethyl,
e) unsubstituted or substituted heteroaryl,
f) unsubstituted or substituted aralkyl,
g) unsubstituted or substituted aryl, and
h) unsubstituted or substituted heterocyclylalkyl;
R11 is independently selected from
a) unsubstituted or substituted C1-6 alkyl,
b) unsubstituted or substituted aralkyl,
c) unsubstituted or substituted heterocycle,
d) unsubstituted or substituted aryl, and
e) unsubstituted or substituted heterocyclylalkyl;
R13 is independently selected from
a) H,
b) unsubstituted or substituted C1-C6 alkyl,
c) unsubstituted or substituted C2-C6 alkenyl,
d) unsubstituted or substituted C2-C6 alkynyl,
e) unsubstituted or substituted aryl,
f) unsubstituted or substituted heterocycle,
g) aralkyl, unsubstituted or substituted,
h) heterocyclylalkyl, unsubstituted or substituted,
i) CF3,
j) CF3Oxe2x80x94,
k) CF3CH2xe2x80x94,
l) C3-C10 cycloalkyl, unsubstituted or substituted,
m) OR10,
n) xe2x80x94C(O)R10,
o) xe2x80x94O(C1-C6 alkyl)OR10,
p) xe2x80x94C(O)NR6R7,
q) xe2x80x94(C1-C6 alkyl)OR10, and
r) xe2x80x94(C1-6 alkyl)C(O)R10;
G1 and G2 are independently selected from oxygen or H2;
V is selected from
a) a bond,
b) heterocycle,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S(O)m, and N, and
e) C2-C20 alkenyl;
W is a heterocycle;
Y1 and Y2 are independently selected from
a) a bond,
b) C1-C8 alkyl,
c) C2-C3 alkenyl,
d) C2-C8 alkynyl,
e) C3-C20 cycloalkyl,
f) aryl, and
g) heterocycle;
Z1 and Z2 are independently selected from
a) a bond,
b) O,
c) C(O),
d) S(O)m,
e) C(O)NR10,
f) (C(R1a)2)n,
g) (C(R1a)2)nO,
h) O(C(R1a)2)n, and
i) NR10;
m is 0, 1 or 2;
n is 0, 1, 2, 3, 4, 5or 6;
p is 0, 1, 2, 3, 4, 5or 6;
q is 0, 1, 2, 3, 4, 5or 6;
r is 0 to 5, provided that r is 0 when V is a bond;
s is 0, 1, 2, 3 or 4; provided that s is 0 when W is a bond;
t is 0, 1, 2, 3 or 4; provided that t is 0 when Y1 is a bond;
u is 4or 5;
v is 0, 1, 2, 3or 4;and
w is 0, 1, 2, 3or 4;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
Another embodiment of the compounds of this invention is illustrated by formula A: 
wherein
X1 is (C(R1c)2)nA1(C(R1c)2)nA2;
X2 is (C(R1b)2)pA3(C(R1b)2)p;
X3 i (C(R1c)2)qA4; 
R1a and R1b are independently selected from:
a) hydrogen;
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, R10Oxe2x80x94, R6aS(O)m, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, xe2x80x94C(O)NR6R7, C(O)NR10xe2x80x94, (R10)2NC(O)NR10xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, R10OC(O)xe2x80x94, and R10OC(O)NR10xe2x80x94, and
c) unsubstituted or substituted C1-C6 alkyl, wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C 10cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, R10Oxe2x80x94, R6aS(O)m, R10C(O)NR10xe2x80x94, (R10)2NC(O)NR10xe2x80x94, xe2x80x94C(O)NR6R7, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, halo, xe2x80x94N(R10)2, and R10OC(O)NR10xe2x80x94;
R1c is selected from
a) hydrogen and
b) unsubstituted or substituted C1-C6 alkyl, wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, R10Oxe2x80x94, R6aS(O)m, xe2x80x94C(O)NR6R7, R10C(O)NR10xe2x80x94, (R10)2NC(O)NR10xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, halo, xe2x80x94N(R10)2, and R10OC(O)NR10xe2x80x94;
A1 and A3 are independently selected from
a) a bond,
b) xe2x80x94C(xe2x95x90O)xe2x80x94,
c) O,
d) NR10,
e) NR10C(O),
f) C(O)NR10,
g) OC(O)NR10,
h) NR10C(O)O,
i) S(xe2x95x90O)m,
j) OC(O), and
k) C(O)O;
A2 is selected from
a) a bond,
b) xe2x80x94C(xe2x95x90O)xe2x80x94,
c) NR10C(O), and
d) S(xe2x95x90O)m;
A4 is a bond;
R2 is independently selected from:
a) hydrogen,
b) CN,
c) NO2,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heterocycle, unsubstituted or substituted,
g) C1-C6 alkyl, unsubstituted or substituted,
h) OR10,
i) N3,
j) R6aS(O)m,
k) C3-C10 cycloalkyl, unsubstituted or substituted,
l) C2-C6 alkenyl, unsubstituted or substituted,
m) C2-C6 alkynyl, unsubstituted or substituted,
n) (R10)2NC(O)NR10xe2x80x94,
o) R10C(O)xe2x80x94,
p) R C(O)NR10xe2x80x94,
q) R10OC(O)xe2x80x94,
r) xe2x80x94N(R10)2;
s) R10OC(O)NR10xe2x80x94, and
t) xe2x80x94(C1-C6 alkyl)NR10C(O)R13;
R3 is independently selected from:
xe2x80x83H, CN, NO2, halo, unsubstituted or substituted C1-C6 alkyl, N3, oxido, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted aralkyl, unsubstituted or substituted heterocyclylalkyl, C1-C6 perfluoroalkyl, CF3Oxe2x80x94, CF3CH2xe2x80x94, unsubstituted or substituted C3-C10 cycloalkyl, OR10, NR6R7, OR6, xe2x80x94C(O)R10, xe2x80x94O(C1-C6 alkyl)OR10, xe2x80x94S(O)mR6a, xe2x80x94C(O)NR6R7, xe2x80x94NHC(O)R10, xe2x80x94(C1-C6 alkyl)OR10, and xe2x80x94(C1-C6 alkyl)C(O)R10;
R4 and R5 are independently selected from:
xe2x80x83H, OR10, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, 
xe2x80x83wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-C6 alkyl,
b) (CH2)nOR6,
c) (CH2)nNR6R7,
d) halogen,
e) CN,
f) aryl or heteroaryl,
g) perfluoro-C1-C4 alkyl,
h) S(O)mR6a,
2) C3-C6 cycloalkyl,
3) OR,
4) S(O)mR6a, 
15) N3,
16) halo, and
17) perfluoro-C1-4-alkyl; or
R4 and R5 are attached to the same C atom and are combined to form xe2x80x94(CH2)uxe2x80x94 wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, NR10, xe2x80x94NC(O)xe2x80x94, and xe2x80x94N(COR10)xe2x80x94;
and any of R4 and R5 are optionally attached to the same carbon atom;
R6, R7 and R7a are independently selected from:
xe2x80x83H, C1-C6 alkyl, C3-C6 cycloalkyl, heterocycle, aryl, aralkyl, aroyl, heteraroyl, arylsulfonyl, heteroarylsulfonyl, C1-C4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from:
a) C1-C6 alkoxy,
b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
c) halogen,
d) HO, 
g) xe2x80x94S(O)mR6a, or
h) N(R10)2; or
R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;
R6a is selected from
a) C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with one or more of the following:
1) C1-4 alkoxy,
2) aryl or heterocycle,
3) halogen,
4) HO, 
6) SO2R6a,
7) N(R10)2; and
b) C1-C6 alkyl, unsubstituted or substituted with one or more of the following:
b 1) xe2x80x94C(R10)2C1-4 alkoxy,
2) aryl or heterocycle,
3) xe2x80x94C(R10)2halogen,
4) xe2x80x94C(R10)2OH, 
6) xe2x80x94C(R10)2SO2R6a, and
7) xe2x80x94C(R10)2N(R10)2;
R8 is independently selected from
a) hydrogen,
b) unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C4 perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, CN, R6aS(O)mxe2x80x94, xe2x80x94C(O)NR6R7, R10C(O)NR10xe2x80x94, NO2, (R10)2NC(O)NR10xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, R10OC(O)NR10xe2x80x94, N3, or xe2x80x94N(R10)2, and
c) C1-C6 alkyl, unsubstituted or substituted by C1-C4 perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R6aS(O)mxe2x80x94, R10C(O)NR10xe2x80x94, xe2x80x94C(O)NR6R7, CN, (R10)2NC(O)NR10, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, and R10OC(O)NR10xe2x80x94;
R9 is independently selected from
1) H, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted aryl, and unsubstituted or substituted heterocycle, wherein the substituted group is substituted with one or more of:
a) C1-C6 alkyl, unsubstituted or substituted,
b) (CH2)nOR6,
c) (CH2)nNR6R7,
d) halogen,
e) CN,
f) aryl, unsubstituted or substituted,
g) heterocycle, unsubstituted or substituted,
h) perfluoro-C1-C4 alkyl,
i) S(O)mR6a,
j) N(R10)2,
k) NR10C(O)R11,
l) NR10OC(O)R11N(R10)2,
2) C3-C6 cycloalkyl,
3) S(O)1-2R6a, 
8) xe2x80x94(C1-C6 alkyl)NR10C(O)R13;
R10 is independently selected from
a) hydrogen,
b) unsubstituted or substituted C1-C6 alkyl,
c) C3-C6 cycloalkyl,
d) 2,2,2-trifluoroethyl,
e) unsubstituted or substituted heteroaryl,
f) unsubstituted or substituted aryl,
g) unsubstituted or substituted aralkyl, and
h) unsubstituted or substituted heterocyclylalkyl;
R11 is independently selected from
a) unsubstituted or substituted C1-C6 alkyl,
b) unsubstituted or substituted aralkyl,
c) unsubstituted or substituted heterocycle,
d) unsubstituted or substituted aryl, and
e) unsubstituted or substituted heterocyclylalkyl;
R13 is independently selected from
a) H,
b) unsubstituted or substituted C1-C6 alkyl,
c) unsubstituted or substituted C2-C6 alkenyl,
d) unsubstituted or substituted C2-C6 alkynyl,
e) unsubstituted or substituted aryl,
f) unsubstituted or substituted heterocycle,
g) aralkyl, unsubstituted or substituted,
h) heterocyclylalkyl, unsubstituted or substituted,
i) CF3,
j) CF3Oxe2x80x94,
k) CF3CH2xe2x80x94,
l) C3-C10 cycloalkyl, unsubstituted or substituted,
m) OR10,
n) xe2x80x94C(O)R10,
o) xe2x80x94O(C1-C6 alkyl)OR10,
p) xe2x80x94C(O)NR6R7,
q) xe2x80x94(C1-C6 alkyl)OR10, and
r) xe2x80x94(C1-C6 alkyl)C(O)R10;
G1 and G2 are independently selected from oxygen or H2;
V is selected from
a) heterocycle,
b) aryl, and
c) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S(O)m, and N,
W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl,
Y1 is selected from
a) a bond,
b) C1-C8 alkyl,
c) C3-C20 cycloalkyl,
d) aryl or
e) heterocycle;
Y2 is selected from
a) a bond,
b) aryl or
c) heterocycle;
Z1 is selected from
a) a bond,
b) O,
c) C(O),
d) S(O)m,
e) C(O)NR10,
f) (C(R1a)2)n,
g) O(C(R1a)2)n,
h) (C(R1a)2)nO, and
i) NR10;
Z2 is selected from:
a) a bond,
b) O,
c) C(O),
d) S(O)m,
e) (C(R1a)2)n, and
f) NR10;
m is 0, 1 or 2;
n is 0, 1, 2, 3, 4, 5 or 6;
p is 0, 1, 2, 3 ,4, 5 or 6;
q is 0, 1, 2, or 3;
r is 0 to 5;
s is 0, 1, 2, 3 or 4;
t is 0, 1, 2, 3 or 4, provided t is 0 when Y1 is a bond;
u is 4 or 5;
v is 0, 1, 2, 3 or 4; and
w is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
Another embodiment of the compounds of this invention is illustrated by the formula B: 
wherein
X1 is (C(R1a)2)nA1(C(R1a)2)nA2;
R1a is selected from:
a) hydrogen;
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, R10Oxe2x80x94, R6aS(O)m, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, xe2x80x94C(O)NR6R7, R10C(O)NR10xe2x80x94, (R10)2NC(O)NR10xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, R10OC(O)xe2x80x94, and R10OC(O)NR10xe2x80x94, and
c) unsubstituted or substituted C1-C6 alkyl, wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, R10Oxe2x80x94, R6aS(O)m, R10C(O)NR10xe2x80x94, xe2x80x94(C(O)NR6R7, (R10)2NC(O)NR10xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, halo, xe2x80x94N(R10)2, and R10OC(O)NR10xe2x80x94;
R1b and R1c are independently selected from
a) hydrogen and
b) unsubstituted or substituted C1-C6 alkyl, wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, R10Oxe2x80x94, R6aS(O)m, xe2x80x94(C(O)NR6R7, R10C(O)NR10, (R10)2NC(O)NR10xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, halo, xe2x80x94N(R10)2, and R10OC(O)NR10xe2x80x94;
A1 is selected from
a) a bond,
b) xe2x80x94C(xe2x95x90O)xe2x80x94,
c) O,
d) NR10,
e) NR10C(O),
f) C(O)NR10,
g) OC(O)NR10,
h) NR10C(O)O,
i) S(xe2x95x90O)m,
j) C(O)O, and
k) OC(O);
A2 is selected from
a) a bond,
b) xe2x80x94C(xe2x95x90O)xe2x80x94,
c) NR10C(O), and
d) S(xe2x95x90O)m;
A3 is selected from a bond or C(xe2x95x90O);
R2 is independently selected from:
a) hydrogen,
b) CN,
c) NO2,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heterocycle, unsubstituted or substituted,
g) C1-C6 alkyl, unsubstituted or substituted,
h) OR10,
i) N3,
j) R6aS(O)m,
k) C3-C10 cycloalkyl, unsubstituted or substituted,
l) C2-C6 alkenyl, unsubstituted or substituted,
m) C2-C6 alkynyl, unsubstituted or substituted,
n) (R10)2NC(O)NRO10xe2x80x94,
o) R10C(O)xe2x80x94,
p) R10C(O)NR10xe2x80x94,
q) R10OC(O)xe2x80x94,
r) xe2x80x94N(R10)2,
s) R10OC(O)NR10xe2x80x94, and
t) xe2x80x94(C1-C6 alkyl)NR10C(O)R13;
R3 is independently selected from:
xe2x80x83H, CN, NO2, halo, unsubstituted or substituted C1-C6 alkyl, N3, oxido, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted aralkyl, unsubstituted or substituted heterocyclylalkyl, C1-C6 perfluoroalkyl, CF3Oxe2x80x94, CF3CH2xe2x80x94, unsubstituted or substituted C3-C10 cycloalkyl, OR10O, NR6R7, OR6, xe2x80x94C(O)R10, xe2x80x94O(C1-C6 alkyl)OR10, xe2x80x94S(O)mR6a, xe2x80x94C(O)NR6R7, xe2x80x94NHC(O)R10, xe2x80x94(C1-C6 alkyl)OR10, and xe2x80x94(C1-C6 alkyl)C(O)R10;
R4 and R5 are independently selected from:
xe2x80x83H, OR10, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, wherein the substituted group is substituted with one or two of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-C6 alkyl,
b) (CH2)nOR6,
c) (CH2)nNR6R7,
d) halogen,
e) CN,
f) aryl or heteroaryl,
g) perfluoro-C1-C4 alkyl,
h) S(O)mR6a,
2) C3-C6 cycloalkyl,
3) OR6,
4) S(O)mR6a, 
15) N3,
16) halo, and
17) perfluoro-C1-4-alkyl; or
R4 and R5 are attached to the same C atom and are combined to form xe2x80x94(CH2)uxe2x80x94 wherein one of the carbon atoms is optionally replaced by a moiety selected from: O,S(O)m, NR10, xe2x80x94NC(O)xe2x80x94-and xe2x80x94N(COR10)xe2x80x94:
and any of R4 and R5 are optionally attached to the same carbon atom;
R6, R7 and R7a are independently selected from:
xe2x80x83H, C1-C6 alkyl, C3-C6 cycloalkyl, heterocycle, aryl, aralkyl, aroyl, heteraroyl, arylsulfonyl, heteroarylsulfonyl, C1-C4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from:
a) C1-C6 alkoxy,
b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
c) halogen,
d) HO, 
g) xe2x80x94S(O)mR6a, or
h) N(R10)2; or
R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;
R6a is selected from
a) C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with one or more of the following:
1) C1-4 alkoxy,
2) aryl or heterocycle,
3) halogen,
4) HO, 
6) SO2R6a,
7) N(R10)2; and
b) C1-C6 alkyl, unsubstituted or substituted with one or more of the following:
1) xe2x80x94C(R10)2C1-4 alkoxy,
2) aryl or heterocycle,
3) xe2x80x94C(R10)2halogen,
4) xe2x80x94C(R10)2OH, 
6) xe2x80x94C(R10)2SO2R6a, and
7) xe2x80x94C(R10)2N(R10)2;
R8 is independently selected from
a) hydrogen,
b) unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C4perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, CN, R6aS(O)m, xe2x80x94C(O)NR6R7, R10C(O)NR10xe2x80x94, NO2, (R10)2NC(O)NR10xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, R10OC(O)NR10xe2x80x94, N3, or xe2x80x94N(R10)2, and
c) C1-C6 alkyl, unsubstituted or substituted by C1-C4 perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R6aS(O)mxe2x80x94, R10C(O)NR10xe2x80x94, xe2x80x94C(O)NR6R7, CN, (R10)2NC(O)NR10xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, and R10OC(O)NR10xe2x80x94;
R9 is independently selected from
1) H, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C, alkynyl, unsubstituted or substituted aryl, and unsubstituted or substituted heterocycle, wherein the substituted group is substituted with one or more of:
a) C1-C6 alkyl, unsubstituted or substituted,
b) (CH2)nOR6,
c) (CH2)nNR6R7,
d) halogen,
e) CN,
f) aryl, unsubstituted or substituted,
g) heterocycle, unsubstituted or substituted,
h) perfluoro-C1-C4 alkyl,
i) S(O)mR6a,
j) N(R10)2,
k) NR10C(O)R11,
l) NR10C(O)R11N(R10)2,
2) C3-C6 cycloalkyl,
3) S(O)1-2R6a, 
8) xe2x80x94(C1-C6 alkyl)NR10C(O)R13;
R10 is independently selected from
a) hydrogen,
b) unsubstituted or substituted C1-C6 alkyl,
c) C3-C6 cycloalkyl,
d) 2,2,2-trifluoroethyl,
e) unsubstituted or substituted heteroaryl,
f) unsubstituted or substituted aryl,
g) unsubstituted or substituted aralkyl, and
h) unsubstituted or substituted heterocyclylalkyl;
R11 is independently selected from
a) unsubstituted or substituted C1-C6 alkyl,
b) unsubstituted or substituted aralkyl,
c) unsubstituted or substituted heterocycle,
d) unsubstituted or substituted aryl, and
e) unsubstituted or substituted heterocyclylalkyl;
R13 is independently selected from
a) H,
b) unsubstituted or substituted C1-C6 alkyl,
c) unsubstituted or substituted C2-C6 alkenyl,
d) unsubstituted or substituted C2-C6 alkynyl,
e) unsubstituted or substituted aryl,
f) unsubstituted or substituted heterocycle,
g) aralkyl, unsubstituted or substituted,
h) heterocyclylalkyl, unsubstituted or substituted,
i) CF3,
j) CF3Oxe2x80x94,
k) CF3CH2xe2x80x94,
l) C3-C10 cycloalkyl, unsubstituted or substituted,
m) OR10,
n) xe2x80x94C(O)R10,
o) xe2x80x94O(C1-C6 alkyl)OR10,
p) xe2x80x94C(O)NR6R7,
q) xe2x80x94(C1-C6 alkyl)OR10, and
r) xe2x80x94(C1-C6 alkyl)C(O)R10;
G1 and G2 are independently selected from oxygen or H2;
V is aryl;
W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl,
Y1 is selected from
a) a bond,
b) C1-C8 alkyl,
c) C3-C20 cycloalkyl,
d) aryl or
e) heterocycle,
Z1 is selected from
a) a bond,
b) O,
c) C(O),
d) S(O)m,
e) (C(R1a)2)n, and
f) NR10;
m is 0, 1 or 2;
n is 0, 1, 2, 3, 4, 5 or 6;
p is 0, 1, 2, 3, or 4;
q is 0, 1, 2, or 3;
r is 0 to 5;
s is 0, 1, 2, 3 or 4;
t is 0, 1, 2, 3 or 4, provided t is 0 when Y1 is a bond;
u is 4 or 5;
v is 0, 1, 2, 3 or 4; and
w is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
Another embodiment of the compounds of this invention is illustrated by the formula C: 
wherein
X1 is (C(R1a)2)nA1(C(R1a)2)nA2;
R1a is selected from:
a) hydrogen;
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, R10Oxe2x80x94, R6aS(O)m, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, R10C(O)NR10xe2x80x94, xe2x80x94C(O)NR6R7, (R10)2NC(O)NR10, R10C(O)xe2x80x94, xe2x80x94N(R10)2, R10OC(O)xe2x80x94, and R10OC(O)NR10xe2x80x94, and
c) unsubstituted or substituted C1-C6 alkyl, wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, R10Oxe2x80x94, R6aS(O)m, R10C(O)NR10xe2x80x94, xe2x80x94C(O)NR6R7, (R10)2NC(O)NR10xe2x80x94, R10OC(O)xe2x80x94, R10OC(O)xe2x80x94, halo, xe2x80x94N(R10)2, and R10OC(O)NR10xe2x80x94;
R1b and R1c are independently selected from
a) hydrogen and
b) unsubstituted or substituted C1-C6 alkyl, wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, R10Oxe2x80x94, R6aS(O)m, R10C(O)NR10xe2x80x94, xe2x80x94C(O)NR6R7, (R10)2NC(O)NR10xe2x80x94, R10OC(O)xe2x80x94, R10OC(O)xe2x80x94, halo, xe2x80x94N(R10)2, and R10OC(O)NR10xe2x80x94;
A1 is selected from
a) a bond,
b) xe2x80x94C(xe2x95x90O)xe2x80x94,
c) O,
d) NR10
e) NR10C(O),
f) C(O)NR10,
g) OC(O)NR10,
h) NR10C(O)O,
i) S(xe2x95x90O)m,
j) C(O)O, and
k) OC(O);
A2 is selected from
a) a bond,
b) xe2x80x94C(xe2x95x90O)xe2x80x94,
c) NR10C(O), and
d) S(xe2x95x90O)m;
A3 is selected from
a) a bond, or
b) C(xe2x95x90O);
R2 is independently selected from:
a) hydrogen,
b) CN,
c) NO2,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heterocycle, unsubstituted or substituted,
g) C1-C6 alkyl, unsubstituted or substituted,
h) OR10,
i) N3,
j) R6aS(O)m,
k) C3-C10 cycloalkyl, unsubstituted or substituted,
l) C2-C6 alkenyl, unsubstituted or substituted,
m) C2-C6 alkynyl, unsubstituted or substituted,
n) (R10)2NC(O)NR10xe2x80x94,
o) R10C(O)xe2x80x94,
p) R10C(O)NR10xe2x80x94,
q) R10OC(O)xe2x80x94,
r) xe2x80x94N(R10)2,
s) R10OC(O)NR10xe2x80x94, and
t) xe2x80x94(C1-C6 alkyl)NR10C(O)R13;
R3 is independently selected from:
xe2x80x83H, CN, NO2, halo, unsubstituted or substituted C1-C6 alkyl, N3, oxido, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted aralkyl, unsubstituted or substituted heterocyclylalkyl, C1-C6 perfluoroalkyl, CF3Oxe2x80x94CF3CH2xe2x80x94, unsubstituted or substituted C3-C10 cycloalkyl, OR10, NR6R7, OR6, xe2x80x94C(O)R10, xe2x80x94O(C1-C6 alkyl)OR10, xe2x80x94S(O)mR6a, xe2x80x94C(O)NR6R7, xe2x80x94NHC(O)R10, xe2x80x94(C1-C6 alkyl)OR10, and xe2x80x94(C1-C6 alkyl)C(O)R10;
R4 and R5 are independently selected from:
xe2x80x83H, OR10, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, wherein the substituted group is substituted with one or two of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-C6 alkyl,
b) (CH2)nOR6,
c) (CH2)nNR6R7,
d) halogen,
e) CN,
f) aryl or heteroaryl,
g) perfluoro-C1-C4 alkyl,
h) S(O)mR6a,
2) C3-C6 cycloalkyl,
3) OR6, 
8) halo, and
9) perfluoro-C1-4-alkyl; or
R4 and R5 are attached to the same C atom and are combined to form xe2x80x94(CH2)uxe2x80x94 wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, NR10, xe2x80x94NC(O)xe2x80x94, and xe2x80x94N(COR10)xe2x80x94;
and any of R4 and R5 are optionally attached to the same carbon atom;
R6, R7 and R8 are independently selected from:
xe2x80x83H, C1-C6 alkyl, C3-C6 cycloalkyl, heterocycle, aryl, aralkyl, C1-C4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from:
a) C1-C6 alkoxy,
b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
c) halogen,
d) HO, 
g) xe2x80x94S(O)mR6a, or
h) N(R10)2; or
R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;
R6a is selected from
a) C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with one or more of the following:
1) C1-4 alkoxy,
2) aryl or heterocycle,
3) halogen,
4) HO, 
6) SO2R6a,
7) N(R10)2; and
b) C1-C6 alkyl, unsubstituted or substituted with one or more of the following:
1) xe2x80x94C(R10)2C1-4 alkoxy,
2) aryl or heterocycle,
3) xe2x80x94C(R10)2halogen,
4) xe2x80x94C(R10)2OH, 
6) xe2x80x94C(R10)2SO2R6a, and
7) xe2x80x94C(R10)2N(R10)2;
R8 is independently selected from
a) hydrogen,
b) F, Cl, Br, R10Oxe2x80x94, CN, R6aS(O)mxe2x80x94, R10C(O)NR10xe2x80x94, xe2x80x94C(O)NR6R7, NO2, (R10)2NC(O)NR10xe2x80x94, R10C(O)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)NR10xe2x80x94, N3, or xe2x80x94N(R10)2 and
c) C1-C6 alkyl, unsubstituted or substituted by C1-C4 perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R6aS(O)mxe2x80x94, R10C(O)NR10xe2x80x94, xe2x80x94C(O)NR6R7, CN, (R10)2NC(O)NR10xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, and R10OC(O)NR10xe2x80x94;
R9 is independently selected from
1) H, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted aryl, and unsubstituted or substituted heterocycle, wherein the substituted group is substituted with one or more of:
a) C1-C6 alkyl, unsubstituted or substituted,
b) (CH2)nOR6,
c) (CH2)nNR6R7,
d) halogen,
e) CN,
f) aryl, unsubstituted or substituted,
g) heterocycle, unsubstituted or substituted,
h) perfluoro-C1-C4 alkyl,
i) S(O)mR6a,
j) N(R10)2,
k) NR10C(O)R11,
l) NR10C(O)R11N(R10)2,
2) C3-C6 cycloalkyl,
3) S(O)1-2R6a, 
8) xe2x80x94(C1-C6 alkyl)NR10C(O)R13;
R10 is independently selected from
a) hydrogen,
b) unsubstituted or substituted C1-C6 alkyl,
c) C3-C6 cycloalkyl,
d) 2,2,2-trifluoroethyl,
e) unsubstituted or substituted heteroaryl,
f) unsubstituted or substituted aryl,
g) unsubstituted or substituted aralkyl, and
h) unsubstituted or substituted heterocyclylalkyl;
R11 is independently selected from
a) unsubstituted or substituted C1-C6 alkyl,
b) unsubstituted or substituted aralkyl,
c) unsubstituted or substituted heterocycle,
d) unsubstituted or substituted aryl, and
e) unsubstituted or substituted heterocyclylalkyl;
R13 is independently selected from
a) H,
b) unsubstituted or substituted C1-C6 alkyl,
c) unsubstituted or substituted C2-C6 alkenyl,
d) unsubstituted or substituted C2-C6 alkynyl,
e) unsubstituted or substituted aryl,
f) unsubstituted or substituted heterocycle,
g) aralkyl, unsubstituted or substituted,
h) heterocyclylalkyl, unsubstituted or substituted,
i) CF3,
j) CF3Oxe2x80x94,
k) CF3CH2xe2x80x94,
l) C3-C10 cycloalkyl, unsubstituted or substituted,
m) OR10,
n) xe2x80x94C(O)R10,
o) xe2x80x94O(C1-C6 alkyl)OR10,
p) xe2x80x94C(O)NR6R7,
q) xe2x80x94(C1-C6 alkyl)OR10, and
r) xe2x80x94(C1-C6 alkyl)C(O)R10;
G1 and G2 are independently selected from oxygen or H2;
W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl,
Y1 is selected from
a) a bond,
b) C1-C8 alkyl,
c) C3-C20 cycloalkyl,
d) aryl or
e) heterocycle,
Z1 is selected from
a) a bond,
b) O,
c) C(O),
d) S(O)m,
e) (C(R1a)2)n, and
f) NR10;
m is 0, 1 or 2;
n is 0, 1, 2, 3, 4, 5 or 6;
p is 0, 1, 2, 3, or 4;
q is 0, 1, 2, or 3;
r is 0 to 5;
s is 0, 1, 2, 3 or 4;
t is 0, 1, 2, 3 or 4, provided t is 0 when Y1 is a bond;
u is 4 or 5;
v is 0, 1, 2, 3 or 4; and
w is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
Another embodiment of the compounds of this invention is illustrated by formula D: 
wherein
X1is (C(R1a)2)nA1(C(R1a)2)nA2;
R1a is selected from:
a) hydrogen;
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, R10)xe2x80x94, R6aS(O)m, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, xe2x80x94C(O)NR6R7, R10C(O)NR10xe2x80x94, (R10)2NC(O)(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, R10OC(O)xe2x80x94, and R10OC(O)NR10xe2x80x94, and
c) unsubstituted or substituted C1-C6 alkyl, wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocycle , unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, R10Oxe2x80x94, R6aS(O)m, xe2x80x94C(O)NR6R7, R10C(O)NR10xe2x80x94, (R10)2NC(O)NR10xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, halo, xe2x80x94N(R10)2, and R10OC(O)NR10xe2x80x94;
R1b and R1c are independently selected from
a) hydrogen and
b) unsubstituted or substituted C1-C6 alkyl, wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, R10Oxe2x80x94, R6aS(O)m, xe2x80x94C(O)NR6R7, R10C(O)NR10xe2x80x94, (R10)2NC(O)(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, halo, xe2x80x94N(R10)2, and R10OC(O)NR10xe2x80x94;
A1 is selected from
a) a bond,
b) xe2x80x94C(xe2x95x90O)xe2x80x94,
c) O,
d) NR10,
e) NR10C(O),
f) C(O)NR10,
g) OC(O)NR10,
h) NR10C(O)O,
i) S(xe2x95x90O)m,
j) C(O)O, and
k) OC(O);
A2 is selected from
a) a bond,
b) xe2x80x94C(xe2x95x90O)xe2x80x94,
c) NR10C(O), and
d) S(xe2x95x90O)m;
A3 is selected from
a) a bond or
b) C(xe2x95x90O);
R2is independently selected from:
a) hydrogen,
b) CN,
c) NO2,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heterocycle, unsubstituted or substituted,
g) C1-C6 alkyl, unsubstituted or substituted,
h) OR10,
i) N3,
j) R6aS(O)m,
k) C3-C10 cycloalkyl, unsubstituted or substituted,
l) C2-C6 alkenyl, unsubstituted or substituted,
m) C2-C6 alkynyl, unsubstituted or substituted,
n) (R10)2NC(O)NR10xe2x80x94,
o) R10C(O)xe2x80x94,
p) R10C(O)NR10xe2x80x94,
q) R10OC(O)xe2x80x94,
r) xe2x80x94N(R10)2,
s) R10OC(O)NR10xe2x80x94, and
t) xe2x80x94(C1-C6 alkyl)NR10C(O)R13;
R3 is independently selected from:
xe2x80x83H, CN, NO2, halo, unsubstituted or substituted C1-C6 alkyl, N3, oxido, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted aralkyl, unsubstituted or substituted heterocyclylalkyl, C1-C6 perfluoroalkyl, CF3Oxe2x80x94, CF3CH2xe2x80x94, unsubstituted or substituted C3-C10 cycloalkyl, OR10, NR6R7, OR6, xe2x80x94C(O)R10, xe2x80x94O(C1-C6 alkyl)OR10, xe2x80x94S(O)mR6a, xe2x80x94C(O)NR6R7, xe2x80x94NHC(O)R10, xe2x80x94(C1-C6 alkyl)OR10, and xe2x80x94(C1-C6 alkyl)C(O)R10;
R4 and R5 are independently selected from:
xe2x80x83H, OR10, unsubstituted or substituted C1-C6 alkyl, wherein the substituted group is substituted with one or two of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-C6 alkyl,
b) (CH2)nOR6,
c) (CH2)nNR6R7,
d) halogen,
e) CN,
f) aryl or heteroaryl,
g) perfluoro-C1-C4 alkyl,
h) S(O)mR6a,
2) C3-C6 cycloalkyl,
3) OR6,
4) xe2x80x94NR6R7, 
6) halo, and
7) perfluoro-C1-4alkyl; or
R4 and R5 are attached to the same C atom and are combined to form xe2x80x94(CH2)uxe2x80x94 wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, NR10, xe2x80x94NC(O)xe2x80x94, and xe2x80x94N(COR10)xe2x80x94;
and any of R4 and R5 are optionally attached to the same carbon atom;
R6, R7 and R7a are independently selected from:
xe2x80x83H, C1-C6 alkyl, C3-C6 cycloalkyl, heterocycle, aryl, aralkyl, C1-C4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from:
a) C1-C6 alkoxy,
b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
c) halogen,
d) HO, 
g) xe2x80x94S(O)mR6a, or
h) N(R10)2; or
R6 and R7 may be joined in a ring;
R7 and R7 amay be joined in a ring;
R6a is selected from
a) C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with one or more of the following:
1) C1-4 alkoxy,
2) aryl or heterocycle,
3) halogen,
4) HO, 
6) SO2R6a,
7) N(R10)2; and
b) C1-C6 alkyl, unsubstituted or substituted with one or more of the following:
1) xe2x80x94C(R10)2C1-4 alkoxy,
2) aryl or heterocycle,
3) xe2x80x94C(R10)2halogen,
4) xe2x80x94C(R10)2OH, 
6) xe2x80x94C(R10)2SO2R6a, and
7) xe2x80x94C(R10)2N(R10)2;
R8 is independently selected from
a) hydrogen, and
b) C1-C6 alkyl, unsubstituted or substituted by C1-C4 perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R6aS(O)m, xe2x80x94C(O)NR6R7, R10C(O)NR10xe2x80x94, CN, (R10)2NC(O)NR10xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, and R10OC(O)NR10xe2x80x94;
R9 is independently selected from
1) H, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted aryl, and unsubstituted or substituted heterocycle, wherein the substituted group is substituted with one or more of:
a) C1-C6 alkyl, unsubstituted or substituted,
b) (CH2)nOR6,
c) (CH2)nNR6R7,
d) halogen,
e) CN,
f) aryl, unsubstituted or substituted,
g) heterocycle, unsubstituted or substituted,
h) perfluoro-C1-C4 alkyl,
i) S(O)mR6a,
j) N(R10)2,
k) NR10C(O)R11,
l) NR10C(O)R11N(R10)2,
2) C3-C6 cycloalkyl,
3) S(O)1-2R6a, 
8) xe2x80x94(C1-C6 alkyl)NR10C(O)R3;
R10 is independently selected from
a) hydrogen,
b) unsubstituted or substituted C1-C6 alkyl,
c) C3-C6 cycloalkyl,
d) 2,2,2-trifluoroethyl,
e) unsubstituted or substituted heteroaryl,
f) unsubstituted or substituted aryl,
g) unsubstituted or substituted aralkyl, and
h) unsubstituted or substituted heterocyclylalkyl;
R11 is independently selected from
a) unsubstituted or substituted C1-C6 alkyl,
b) unsubstituted or substituted aralkyl,
c) unsubstituted or substituted heterocycle,
d) unsubstituted or substituted aryl,
e) unsubstituted or substituted heterocyclylalkyl;
R13 is independently selected from
a) H,
b) unsubstituted or substituted C1-C6 alkyl,
c) unsubstituted or substituted C2-C6 alkenyl,
d) unsubstituted or substituted C2-C6 alkynyl,
e) unsubstituted or substituted aryl,
f) unsubstituted or substituted heterocycle,
g) aralkyl, unsubstituted or substituted,
h) heterocyclylalkyl, unsubstituted or substituted,
i) CF3,
j) CF3Oxe2x80x94,
k) CF3CH2xe2x80x94,
l) C3-C10 cycloalkyl, unsubstituted or substituted,
m) OR10,
n) xe2x80x94C(O)R10,
o) xe2x80x94O(C1-C6 alkyl)OR10,
p) xe2x80x94C(O)NR6R7,
q) xe2x80x94(C1-C6 alkyl)OR10, and
r) xe2x80x94(C1-C6 alkyl)C(O)R10;
G1 is independently selected from oxygen or H2;
Y1 is selected from
a) a bond,
b) C1-C8 alkyl,
c) C3-C20 cycloalkyl,
d) aryl or
e) heterocycle,
Z1 is selected from
a) a bond,
b) O, and
c) C(O);
m is 0, 1 or 2;
n is 0, 1, 2, 3, 4, 5 or 6;
p is 0, 1, 2, 3, or 4;
q is 0, 1, 2, or 3;
r is 0 to 5;
s is 0, 1, 2, 3 or 4;
t is 0, 1, 2, 3 or 4, provided t is 0 when Y1 is a bond;
u is 4 or 5;
v is 0, 1, 2, 3 or 4; and
w is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
Specific compounds of the invention are:
(20R)-19,20,21,22-Tetrahydro-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
(20S)-19,20,21,22-Tetrahydro-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
(20R)-14-Chloro-19,20,21,22-tetrahydro-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatri-azacycloeicosine-9-carbonitrile;
(20S)-14-Chloro-19,20,21,22-tetrahydro-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatri-azacycloeicosine-9-carbonitrile;
(21R)-20,21,22,23-Tetrahydro-17-oxo-5H,17H,19H-18,21-methano-6,10:12,16-dimethenoimidazo[3,4-h][1,8,11,15]oxatriazacycloheneicosine-9-carbonitrile;
(21S)-20,21,22,23-Tetrahydro-17-oxo-5H,17H,19H-18,21-methano-6,10:12,16-dimethenoimidazo[3,4-h][1,8,11,15]oxatriazacycloheneicosine-9-carbonitrile;
(21R)-20,21,22,23-Tetrahydro-5H,19H-18,21-methano-6,10:12,16-dimetheno-16H-imidazo[4,3-n][1,8,12,15,7]oxatriazathia-cycloheneicosine-9-carbonitrile 17,17-dioxide;
(21S)-20,21,22,23-Tetrahydro-5H,19H-18,21-methano-6,10:12,16-dimetheno-16H-imidazo[4,3-n][1,8,12,15,7]oxatriazathia-cycloheneicosine-9-carbonitrile 17,17-dioxide;
(20S)-19,20,21,22-Tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
(20R)-19,20,21,22-Tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
(5R,20R)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile;
(5S,20R)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile;
(5R,20S)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile;
(5S,20S)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile;
(5R,20R)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
(5S,20R)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
(5R,20S)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
(5S,20S)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
(17R,20S)-17-(3-Chlorophenyl)-19,20,21,22-tetrahydro-19-oxo-5H,18H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
(17S,20S)-17-(3-Chlorophenyl)-19,20,21,22-tetrahydro-19-oxo-5H,18H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatniazacycloeicosine-9-carbonitrile;
(17R,20R)-17-(3-Chlorophenyl)-19,20,21,22-tetrahydro-19-oxo-5H,18H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
(17S,20R)-17-(3-Chlorophenyl)-19,20,21,22-tetrahydro-19-oxo-5H,18H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
(17R,20S)-19,20,21,22-Tetrahydro-19-oxo-17-phenyl-5H,18H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile;
(17S,20S)-19,20,21,22-Tetrahydro-19-oxo-17-phenyl-5H,18H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile;
(17R,20R)-19,20,21,22-Tetrahydro-19-oxo-17-phenyl-5H,18H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile;
(17S,20R)-19,20,21,22-Tetrahydro-19-oxo-17-phenyl-5H,18H-18,20-ethano-6,10:12,16-dimetheno-16H-imnidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile;
(20S)-19,20,21,22-Tetrahydro-21-methyl-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
(20R)-19,20,21,22-Tetrahydro-21-methyl-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
(20R)-19,20,22,23-Tetrahydro-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriaza-cyclononadecosine-9-carbonitrile;
(20S)-19,20,22,23-Tetrahydro-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriaza-cyclononadecosine-9-carbonitrile;
(20R)-15-Bromo-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
(20S)-15-Bromo-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
(20R)-15-Cyclopropylethynyl-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
(20S)-15-Cyclopropylethynyl-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
(20S)-15-(2-Cyclopropylethyl)-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
(20R)-15-(2-Cyclopropylethyl)-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
(20R)-19,20,21,22-Tetrahydro-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
(20S)-19,20,21,22-Tetrahydro-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
(20S)-19,20,22,23-Tetrahydro-19-oxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
(20R)-19,20,22,23-Tetrahydro-19-oxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
(5R,20R)-19,20,22,23-Tetrahydro-5-hydroxy-5-methyl-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz [d]imidazo[3,4-l][1,6,9,12]oxatriazacyclononadecosine-9-carbonitrile;
(5S,20R)-19,20,22,23-Tetrahydro-5-hydroxy-5-methyl-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[3,4-l][1,6,9,12]oxatriazacyclononadecosine-9-carbonitrile;
(5S,20S)-19,20,22,23-Tetrahydro-5-hydroxy-5-methyl-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[3,4-l][1,6,9,12]oxatriazacyclononadecosine-9-carbonitrile;
(5R,20S)-19,20,22,23-Tetrahydro-5-hydroxy-5-methyl-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[3,4-l][1,6,9,12]oxatriazacyclononadecosine-9-carbonitrile;
(20S)-19,20,21,22,23,24-hexahydro-19,22-dioxo-5H,18H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-m][1,6,9,14]oxatriazacycloeiscosine-9-carbonitrile;
(20R)-19,20,21,22,23,24-hexahydro-19,22-dioxo-5H,18H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-m][1,6,9,14]oxatriazacycloeiscosine-9-carbonitrile;
(20S)-19,20,21,22,23,24-hexahydro-19-oxo-5H,18H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-m][1,6,9,14]oxatriazacycloeiscosine-9-carbonitrile;
(20R)-19,20,21,22,23,24-hexahydro-19-oxo-5H,18H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-m][1,6,9,14]oxatriazacycloeiscosine-9-carbonitrile;
15-Bromo-19,20,21,22-tetrahydro-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
(17R,20R)-19,20,21,22-tetrahydro-19-oxo-17H-15,17:18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
(17S,20R)-19,20,21,22-tetrahydro-19-oxo-17H-15,17:18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
(17S,20S)-19,20,21,22-tetrahydro-19-oxo-17H-15,17:18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
(17R,20S)-19,20,21,22-tetrahydro-19-oxo-17H-15,17: 18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
(20S)-19,20,22,23-Tetrahydro-21-methyl-19-oxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
(20R)-19,20,22,23-Tetrahydro-21-methyl-19-oxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
(17R,20R)-19,20,21,22-tetrahydro-21-methyl-19-oxo-17H-15,17:18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
(17S,20R)-19,20,21,22-tetrahydro-21-methyl-19-oxo-17H-15,17:18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
(17S,20S)-19,20,21,22-tetrahydro-21-methyl-19-oxo-17H-15,17:18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
(17R,20S)-19,20,21,22-tetrahydro-21-methyl-19-oxo-17H-15,17:18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
(20R)-16-bromo-19,20,22,23-tetrahydro-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
(20S)-16-bromo-19,20,22,23-tetrahydro-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
(23S)-22,23,24,25-tetrahydro-22-oxo-16H,21H-21H,23-ethano-6,10:12,16-dimethenobenz[g]imidazo[4,3-n][1,9,12,1]oxatriazacycloheneicosine-9-carbosntrile;
(23R)-22,23,24,25-tetrahydro-22-oxo-16H,21H-21,23-ethano-6,10:12,16-dimethenobenz[g]imidazo[4,3-n][1,9,12,15]oxatriazacycloheneicosine-9-carbonitrile;
(20S)-25-aza-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
(20R)-25-aza-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
(20S)-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,3,6,9,12]oxatetraaza-cyclooctadecosine-9-carbonitrile;
(20R)-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,3,6,9,12]oxatetraaza-cyclooctadecosine-9-carbonitrile;
(21S)-19,20,22,23-tetrahydro-18-oxo-5H,21H-19,21-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,7,10,13]oxatriazacyclononadecosine-9-carbonitrile;
(21R)-19,20,22,23-tetrahydro-18-oxo-5H,21H-19,21-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,7,10,13]oxatriazacyclononadecosine-9-carbonitrile;
(20S)-19,20,21,22-tetrahydro-3-methyl-19-oxo-5H-18,20-ethano-12, 14-etheno-6,10-metheno-18H-benz[d]imnidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
(20R)-19,20,21,22-tetrahydro-3-methyl-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
(20S)-19,20,22,23-tetrahydro-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz [d]imidazo[4,3-i][1,6,9,13]oxatriazacyclonon adecosine-9-carbonitrile;
(20R)-19,20,22,23-tetrahydro-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
(21S)-19,20,22,23,24-pentahydro-18-oxo-5H,21H-19,21-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-m][1,7,10,14]oxatriazacycloeicosine-9-carbonitrile;
(21R)-19,20,22,23,24-pentahydro-18-oxo-5H,21H-19,21-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-m][1,7,10,14]oxatriazacycloeicosine-9-carbonitrile;
(20S)-17-bromo-19,20,22,23-tetrahydro-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
(20R)-17-bromo-19,20,22,23-tetrahydro-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
(5S,20S)-5-amino-19,20,22,23-tetrahydro-5-methyl-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[3,4-l][1,6,9,12]oxatriazacyclononadecosine-9-carbonitrile;
(5R,20S)-5-amino-19,20,22,23-tetrahydro-5-methyl-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[3,4-l][1,6,9,12]oxatliazacyclononadecosine-9-carbonitrile;
(5S,20R)-5-amino-19,20,22,23-tetrahydro-5-methyl-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[3,4-l][1,6,9,12]oxattiazacyclononadecosine-9-carbonitrile;
(5R,20R)-5-amino-19,20,22,23-tetrahydro-5-methyl-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[3,4-i][1,6,9,12]oxatriazacyclononadecosine-9-carbonitrile;
(20S)-15,16,17,17a,19,20,21,22-octahydro-15-oxa-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
(20R)-15,16,17,17a,19,20,21,22-octahydro-15-oxa-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
(20S)-15,16,17,17a,19,20,21,22-octahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
(20R)-15,16,17,17a,19,20,21,22-octahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
Specific examples of the compounds of the instant invention are: 
(20R)-19,20,21,22-Tetrahydro-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile; 
(21S)-20,21,22,23-Tetrahydro-5H,19H-18,21-methano-6,10:12,16-dimetheno-16H-imidazo[4,3-n][1,8,12,15,7]oxatriazathia-cycloheneicosine-9-carbonitrile 17,17-dioxide; 
(20S)-19,20,21,22-Tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz [d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile; 
(20R)-15,16,17,17a,19,20,21,22-octahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile; 
(5S,20R)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile; 
(5R,20R)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile; 
(20S)-19,20,22,23-Tetrahydro-19-oxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile; 
(20R)-19,20,22,23-Tetrahydro-19-oxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile; 
(17R,20R)-19,20,21,22-tetrahydro-19-oxo-17H-15,17:18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile; 
(20R)-15,16,17,17a,19,20,21,22-octahydro-15-oxa-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
The compounds of the present invention may have asymmetric centers, chiral axes and chiral planes, and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. (See E. L. Eliel and S. H. Wilen Sterochemistry of Carbon Compounds (John Wiley and Sons, New York 1994), in particular pages 1119-1190). When any variable, term or substituent (e.g. aryl, heterocycle, n, R1a, etc.) occurs more than one time in any formula or generic structure, its definition on each occurrence is independent from the definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having 1 to 6 carbon atoms, unless otherwise specified; xe2x80x9calkoxyxe2x80x9d represents an alkyl group having 1 to 6 carbon atoms, unless otherwise indicated, attached through an oxygen bridge. xe2x80x9cHalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein means fluoro, chloro, bromo and iodo. xe2x80x9cCycloalkylxe2x80x9d as used herein is intended to include non-aromatic cyclic hydrocarbon groups, having the specified number of carbon atoms, which may or may not be bridged or structurally constrained. Examples of such cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, cycloheptyl, and the like.
If no number of carbon atoms is specified, the term xe2x80x9calkenylxe2x80x9d refers to a non-aromatic hydrocarbon, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. Thus, xe2x80x9cC2-C6 alkenylxe2x80x9d means an alkenyl radical having from 2 to 6 carbon atoms. Examples of such alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
The term xe2x80x9calkynylxe2x80x9d refrs to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present. Thus, xe2x80x9cC2-C6 alkynylxe2x80x9d means an alkynyl radical having from 2 to 6 carbon atoms. Examples of such alkynyl groups include, but are not limited to, ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
As used herein, xe2x80x9carylxe2x80x9d is intended to mean any stable monocyclic, bicyclic or tricyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, indanonyl, biphenyl, tetralinyl, tetralonyl, fluorenonyl, phenanthryl, anthryl or acenaphthyl.
As used herein, xe2x80x9caralkylxe2x80x9d is intended to mean an aryl moiety, as defined above, attached through a C1-C6 alkyl linker, where alkyl is defined above. Examples of aralkyls include, but are not limited to, benzyl, naphthylmethyl and phenylbutyl.
The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl, chromanyl, cinnolinyl, dibenzofuranyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl, piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl and triazolyl.
As used herein, xe2x80x9cheteroarylxe2x80x9d is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S. Examples of such heteroaryl elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyranyl, benzopyrazolyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furanyl, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, thienyl and triazolyl.
As used herein, xe2x80x9cheterocyclylalkylxe2x80x9d is intended to mean a heterocyclic moiety, as defined above, attached through a C1-C6 alkyl linker, where alkyl is defined above. Examples of heterocyclylalkyls include, but are not limited to, 2-pyridylmethyl, 2-morpholinylethyl, 2-imidazolylethyl, 2-quinolinylmethyl, 2-imidazolylmethyl, 1-piperazineethyl, and the like.
As used herein, the terms xe2x80x9csubstituted alkylxe2x80x9d, xe2x80x9csubstituted alkenylxe2x80x9d, xe2x80x9csubstituted alkynylxe2x80x9d and xe2x80x9csubstituted alkoxyxe2x80x9d are intended to include the branch or straight-chain alkyl group of the specified number of carbon atoms, wherein the carbon atoms may be substituted with one to three of the following substituents: F, Cl, Br, I, CF3, N3, NO2, NH2, oxo, OH, xe2x80x94O(C1-C6 alkyl), S(O)0-2, (C1-C6 alkyl)S(O)0-2xe2x80x94, C2-C6 alkenyl, C2-C6 alkynyl, xe2x80x94(C1-C6 alkyl)S(O)0-2, (C1-C6 alkyl), C3-C20 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, xe2x80x94C(O)NH, (C1-C6 alkyl)C(O)NHxe2x80x94, H2Nxe2x80x94CH(NH)xe2x80x94, H2NC(O)NHxe2x80x94, (C1-C6 alkyl)C(O)xe2x80x94, xe2x80x94O(C1-C6 alkyl)CF3, (C1-C6 alkyl)OC(O)xe2x80x94, (C1-C6 alkyl)O(C1-C6 alkyl)xe2x80x94, (C1-C6 alkyl)C(O)2(C1-C6 alkyl)xe2x80x94, (C1-C6 alkyl)OC(O)NHxe2x80x94, aryl, benzyl, heterocycle, aralkyl, heterocyclylalkyl, halo-aryl, halo-benzyl, halo-heterocycle, cyano-aryl, cyano-benzyl and cyano-heterocycle.
As used herein, the terms xe2x80x9csubstituted arylxe2x80x9d, xe2x80x9csubstituted heterocyclexe2x80x9d, xe2x80x9csubstituted heteroarylxe2x80x9d, xe2x80x9csubstituted cycloalkylxe2x80x9d, xe2x80x9csubstituted benzylxe2x80x9d, xe2x80x9csubstituted aralkylxe2x80x9d and xe2x80x9csubstituted heterocyclylalkylxe2x80x9d are intended to include the cyclic group containing from 1 to 3 substitutents in addition to the point of attachment to the rest of the compound. Such substitutents are preferably selected from the group which includes but is not limited to F, Cl, Br, I, CF3, NH2, N(C1-C6 alkyl)2, NO2, CN, N3, C1-C20 alkyl, C1-C6 alkoxy, C3-C20 cycloalkyl, xe2x80x94OH, xe2x80x94O(C1-C6 alkyl), S(O)0-2, (C1-C6 alkyl)S(O)0-2xe2x80x94, (C1-C6 alkyl)S(O)0-2(C1-C6 alkyl)xe2x80x94, (C1-C6 alkyl)C(O)NHxe2x80x94, H2Nxe2x80x94CH(NH)xe2x80x94, H2Nxe2x80x94C(O)NHxe2x80x94, (C1-C6 alkyl)C(O)xe2x80x94, (C1-C6 alkyl)OC(O)xe2x80x94, (C1-C6 alkyl)O(C1-C6 alkyl)xe2x80x94, (C1-C6)C(O)2(C1-C6 alkyl)xe2x80x94, (C1-C6 alkyl)OC(O)NHxe2x80x94, aryl, aralkyl, heteroaryl, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle and cyano-heterocyclylalkyl.
When R4 and R5 are combined to form xe2x80x94(CH2)uxe2x80x94, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to: 
In addition, with respect to R4 and R5, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to: 
Examples of the ring structures which may be formed when R6 and R7, or R7 and R7a, are joined include, but are not limited to: 
As used herein, examples of xe2x80x9cC3-C20 cycloalkylxe2x80x9d may include, but are not limited to: 
Lines drawn into the ring systems from substituents (such as from R4, R5, X1, etc.) indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms or heteroatoms.
Preferably, R2 is independently selected from H, CN, OR10, halo, unsubstituted or substituted C1-C6 alkyl, xe2x80x94(C1-C6 alkyl)NR10C(O)R13. Most preferably, r is 1 to 3 and at least one R2 is CN.
Preferably, R3 is independently selected from H, halo, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl, xe2x80x94(C1-C6 alkyl)OR10, xe2x80x94O(C1-C6 alkyl)OR10. Most preferably, R3 is H, halo, unsubstituted or substituted C1-C6 alkyl, or unsubstituted or substituted C2-C6 alkynyl.
Preferably, R4 and R5 are independently selected from hydrogen, unsubstituted or substituted C1-C6 alkyl, and OR10. Most preferably, R4 and R5 are independently selected from hydrogen or unsubstituted or substituted C1-C6 alkyl.
Preferably, R8 is selected from hydrogen, or unsubstituted or substituted C1-C6alkyl. Most preferably, R8 is selected from hydrogen or methyl.
Preferably, R9 is selected from hydrogen, unsubstituted or substituted C1-C6 alkyl, and unsubstituted or substituted aryl.
Preferably, R10 is selected from hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heterocycle.
Preferably, A1 is selected from a bond, C(xe2x95x90O), S(xe2x95x90O)m, NR10C(O), or C(O)NR10.
Preferably, A2 is selected from a bond, C(xe2x95x90O), or S(xe2x95x90O)m.
Preferably, A3 is selected from a bond or xe2x80x94C(xe2x95x90O)xe2x80x94.
Preferably, A4 is selected from a bond.
Preferably, G2 is H2.
Preferably, V is aryl or heterocycle. More preferably V is aryl. Most preferably, V is phenyl.
Preferably, W is imidazolyl or pyridyl. Most preferably, W is imidazolyl.
Preferably, X1 represents (C(R1a)2)n, C(O), S(O)m, or a bond.
Preferably, X2 represents (C(R1b)2)p, (CH2)p, C(O)(CH2)p, or a bond.
Preferably, X3 represents (C(R1c)2)q.
Preferably, Y1 is selected from aryl or heterocycle. More preferably, Y1 is phenyl, biphenyl, naphthyl or pyridyl. Most preferably, Y1 is phenyl or naphthyl.
Preferably, Y2 is selected from a bond or heterocycle. Most preferably, Y2 is a bond.
Preferably, Z1 is selected from a bond, (C(R1a)2)n or O. Most preferably, Z1 is O.
Preferably, Z2 is a bond, O, or (C(R1a)2)n. More preferably, Z2 is a bond.
Preferably, variable n is independently selected from 0, 1, 2, 3, or 4. Preferably, variables p and q are independently selected from 0, 1, 2 or 3.
Preferably, the moiety 
represents 
Preferably, the moiety 
represents 
where p is 1 or 2.
It is intended that the definition of any substituent or variable (e.g., R1a, R2, m, p, etc.) at a particular location in a molecule is independent of its definitions elsewhere in that molecule. Thus, xe2x80x94C(R1a)2 can represent xe2x80x94CH2, xe2x80x94CHCH3, xe2x80x94CHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
Abbreviations which may be used in the description of the chemistry and in the Examples that follow include:
These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes. The procedures discussed and illustrated in the following schemes and synopsis may be used in the preparation of the compounds of the instant invention, for either (R) or (S) stereochemistry.
Synopsis of Schemes
Scheme 1 details the synthesis of a representative 3-aminopyrrolidinone. In this case, the benzyl alcohol 1 is converted into the benzyl azide 2 by treatment with DPPA and DBU in toluene. Reduction of this azide by LAH provides the benzylamine, which is coupled to BOC-methionine using PYBOP to provide amide 4. Treatment of compound 4 with excess iodomethane gives the corresponding dimethylsulfonium salt, which can be cyclized to the desired aminopyrrolidinone upon reaction with lithium bis(trimethylsilyl) amide in TBF. Deprotection of this pyrrolidinone 5, by hydrogenolysis followed by treatment with HCl in ethyl acetate, leads to the basic 3-aminopyrrolidinone 6.
Scheme 1A demonstrates the synthesis of an isomeric pyrrolidinone. The synthesis of the 3-aminopyrrolidinone 6a begins by treating the amine 3 and a BOC-protected aspartic acid ethyl ester with PYBOP and DIEA. The resulting amide is treated with Lawesson""s reagent to give the thioamide, which is reduced using NaBH4 and NiCl2 and then cyclized to obtain the intermediate 5a. Using techniques described above, the intermediate 5a is converted to the compound 6a, which may be used as a substitute for the basic 3-aminopyrrolidinone 6 in any of the following schemes.
The synthesis of a key imidazole carboxaldehyde intermediate 10 is shown in Scheme 2. Starting from the bromotoluene derivative 7, a palladiumcatalyzed cyanation reaction, followed by benzylic bromination with NBS, leads to the benzyl bromide 8. This bromide is used to alkylate a trityl-protected imidazole derivative in acetonitrile, and the resulting imidazolium salt is detritylated by treatment with MeOH to provide the 1,5-disubstituted imidazole 9. Saponification of the acetyl ester of 9, followed by modified Swern conditions, leads to the desired aldehyde 10.
The amine 6 and the aldehyde 10 are then coupled via reductive amination, as shown in Scheme 3. The resulting secondary amine 11 is then treated with Cs2CO3 in DMF to give the cyclized product 12.
Scheme 3A illustrates the synthetic strategy that is employed when the R2 substitutent is not an electronic withdrawing moiety either ortho or para to the fluorine atom. In the absence of the electronic withdrawing moiety, the intramolecular cyclization can be accomplished via an Ullmann reaction. Thus, the imidazolylmethylacetate is treated with a suitably substituted halobenzylbromide to provide the 1-benzylimidazolyl intermediate 9a. The acetate functionality of intermediate 9a was converted to an aldehyde which was then reductively coupled to intermediate 9a. Coupling under standard Ullmann conditions provided compound 12a of the instant invention.
Scheme 4 shows the synthesis of a chloro-substituted analog of structure 12. In this case, a 3,5-dichlorophenol is benzylated to give compound 14, which is converted to the corresponding Grignard Reagent followed by quenching with carbon dioxide to provide the benzoic acid 15. Reduction of this acid with LAH provides the corresponding benzyl alcohol 16, and this is subjected to the same sequence of reactions as alcohol 1 in Scheme 1 to ultimately provide the desired macrocycle 23.
In Scheme 5, the hydroxybenzoic acid 24 is coupled to (S)-3-(tert-butoxycarbonylamino)pyrrolidine (commercially available from TCI, U.S.A.) using EDC and HOBT in DMF. The resulting compound 25 is deprotected and then reductively alkylated with aldehyde 10 to provide structure 27. Cyclization of this phenol, with Cs2CO3 as a base, leads to the final product 28.
A sulfonamide analog of compound 28 is shown in Scheme 6. The synthetic sequence begins with bromobenzene 29, which is treated with Mg to provide the Grignard Reagent, which is reacted with sulfur dioxide to give the sulfinate derivative 30. Treatment of this with sulfuryl chloride yields the corresponding sulfonyl chloride, which is reacted with a suitable pyrrolidine derivative to provide sulfonamide 31. Deprotection of this sulfonamide by hydrogenolysis, followed by treatment with HCl in EtOAc, provides the amine hydrochloride 32, and subjection of this to the standard procedures used in the previous schemes gives the desired sulfonamide macrocycle 34.
The synthesis of another derivative of macrocycle 12, in which the benzylic site adjacent to the imidazole is substituted, is shown in Scheme 7. In this example, addition of methylmagnesium bromide to benzaldehyde 35 provides the secondary alcohol 36. A mixture of alcohol 36, a suitably protected imidazole, and DIEA, in dichloromethane is then treated with triflic anhydride to give the imidazolium salt 37 which, after methanolysis, affords compound 38. Cleavage of the silyl ether, then oxidation of the resulting alcohol yields the aldehyde 39, which may be treated analogously to aldehyde 10 to provide the macrocyclic analog 41.
A method for the synthesis of analogs that are substituted at the alternative benzylic position in macrocycle 12 is detailed in Schemes 8 and 9. The route starts with formation of the Grignard Reagent from bromide 29 and reaction of this organometallic derivative with 3-chlorobenzaldehyde. Application of a similar sequence of steps to that described in Scheme 1 converts the alcohol 42 to the pyrrolidinone derivative 46, obtained as a mixture of diastereomers. At this stage, the benzyl protecting group is removed and the diastereomers are separated by chromatography. As depicted in Scheme 8, for diastereomer B, modified cyclization conditions using KF on alumina in acetonitrile yield the final product 50. As shown in Scheme 9, for diastereomer A, application of the standard procedures of deprotection, reductive alkylation, and Cs2CO3-mediated cyclization provides the final product 54. In order to provide simple phenyl-substituted macrocycles, such as structure 54 in Scheme 9, the hydrogenolysis of benzyl ether 46 is conducted under 50 atm of hydrogen pressure in order to concomitantly remove the chloro substituent. The des-chloro derivative 51 is subjected to an analogous sequence to that shown in Scheme 8 to provide the final macrocycle 54.
Scheme 10 illustrates the synthesis of the naphthyl intermediates 63. Following protection of the aminonaphthol 55 with BOC and mesylate groups to give structure 57, treatment with N-bromosuccinimide in acetic acid leads to the bromo derivative 58. The mesylate group is then removed by treatment with NaOH and the liberated phenol is converted to the ten-butyldimethylsilyl ether 59. Standard removal of the carbamate protecting group provides aniline 60 which is then coupled to (R)-BOC-methionine using PYBOP to yield 61. Treatment of compound 61 with excess iodomethane gives the corresponding dimethylsulfonium salt, which can be cyclized to the desired aminopyrrolidinone upon reaction with lithium bis(trimethylsilyl)amide in THF. Deprotection of this pyrrolidinone 62, using TBAF in THF, followed by treatment with HCl in ethyl acetate, leads to the basic 3-aminopyrrolidinone 63.
Synthesis of the macrocyclic pyrrolidinone 65 is depicted in Scheme 11. Intermediate 63 is reductively alkylated with aldehyde 10 to provide the phenol 64. Cyclization of this phenol 64 with cesium carbonate as a base leads to the final product 65.
Scheme 12 shows the synthesis of compound 70. The benzyl bromide 8 is used to alkylate a trityl-protected imidazole derivative in acetonitrile and the resulting imidazolium salt is detritylated by treatment with methanol to provide the 1,5-disubstituted imidazole 66. Treatment of the imidazole 66 with LiOH, in THF and water, yielded the lithium salt 67. The lithium salt 67 is coupled to intermediate 68, using EDC, HOBT, and DIEA in DMF. The resulting compound 69 is then cyclized, using cesium carbonate in DMSO, to provide the final product 70.
Scheme 13 illustrates the alkylation of compound 70 using H2CO and NaCNBH3 in DIEA and methanol, to yield the final product 72.
The synthesis of compound 74 is depicted in Scheme 14. Compound 65 is treated with [2-(tri-n-butylstannyl-1-ethynyl]cyclopropane and tetrakis(triphenylphosphine)palladium in DMF to yield compound 73. Treatment of compound 73 with H2, Pt-C and ethanol produced the final product 74.
Scheme 15 illustrates the synthesis of compound 82. Compound 57 is treated with HCl and EtOAc to provide the amine 75. The amine 75 is then coupled to BOC-methionine using PYBOP and DIEA in CH2Cl2, to yield the intermediate 76. Treatment of intermediate 76 with excess iodomethane gives the corresponding dimethylsulfonium salt, which can be cyclized to the desired aminopyrrolidinone upon reaction with lithium bis(trimethylsilyl)amide in THF. This pyrrolidinone 77 is then treated with Lawesson""s Reagent in toluene to obtain the thioamide 78. Treatment with Raney Ni in ethanol gives the protected pyrrolidine 79. The pyrrolidine 79 is then treated with TBAF and THF, followed by HCl and EtOAc, to yield the deprotected aminopyrrolidine 80. Reductive alkylation of the amino pyrrolidine 80 yields compound 81, which is cyclized, using cesium carbonate and DMF, to the final product 82.
The syntheses of the useful intermediates imidazole 84 and alcohol 86 from previously described compounds are illustrated in Scheme 16A and Scheme 16B, respectively. These intermediates can be utilized in the synthesis of the macrocyclic structure 95, as shown in Scheme 17. Following deprotection, the aminopyrrolidinone 88 is coupled to 84 using standard EDC-mediated conditions. The TBS protecting group is then exchanged for the more robust TBDPS ether, and subsequent reaction with Lawesson""s reagent affords thioamide 91. This thioamide is desulfurized using Raney nickel and the resulting amine is converted to the corresponding tert-butyl carbamate 92. A mixture of 92 and alcohol 86 in CH2Cl2 is then treated with trifluoromethanesulfonic anhydride in the presence of DIEA to provide, after methanolic work-up, compound 93. Standard removal of the silyl ether with TBAF provides the phenol 94, and this is subjected to the normal cyclization and deprotection conditions to afford the final compound 95.
Scheme 18 details the synthesis of compounds with an alternative substitution pattern on the imidazole ring. The iodoimidazole derivative 96 is converted to the corresponding Grignard reagent by treatment with EtMgBr and this organometallic adds to aldehyde 85 to provide the secondary alcohol 97. Oxidation of this to the corresponding ketone is achieved using manganese (IV) oxide, and this ketone is reacted with MeMgBr to provide the tertiary alcohol 99. Alkylation of imidazole 99 with the triflate derived from methyl glycolate, and subsequent methanolysis, affords ester 100, which is saponified using lithium hydroxide. The resulting carboxylate is coupled to aminopyrroldinone 68, and cyclization of the coupled product 102, utilizing cesium carbonate, gives the macrocycle 103.
Syntheses of carboxylic acid 109 and aldehyde 111, which are useful in the preparation of certain macrocyclic compounds, are detailed in Scheme 19. The urocanic acid 104 is esterified by treatment with acidic methanol, and then hydrogenated with a palladium on carbon catalyst to provide the propionate derivative 106. Standard regioselective protection with a trityl group affords compound 107, which is treated with a suitable benzyl bromide to give, after methanolic removal of the trityl group, the ester 108. Saponification of this ester with lithium hydroxide affords the desired acid salt 109. The lithium salt 109 may be converted to the corresponding Weinreb amide using standard EDC-coupling conditions, and reduction of this amide with DIBAL gives aldehyde 111.
Synthesis of compounds of the invention characterized by the incorporation of a third aromatic carbocyclic moiety into the macrocycle is illustrated in Scheme 20. A benzyloxyphenoxyaniline 115, prepared in three steps from a suitably substituted 2-benzyloxyphenol 113 and a suitably substituted 2-nitrobenzene chloride 112, is coupled to BOC-methionine using PYBOP to provide the amide 116. Treatment of the amide 116 with excess iodomethane gives the corresponding dimethylsulfonium salt, which can be cyclized to the desired aminopyrrolidinone 117 upon reaction with lithium bis(trimethylsilyl) amide in THF. Deprotection of this pyrrolidinone 117, by hydrogenolysis followed by treatment with HCl in ethyl acetate, leads to the 3-aminopyrrolidinone 118. The 3-aminopyrrolidinone 118 may then be converted to the final product 120 using techniques described in the above schemes, particularly Scheme 3.
Schemes 21-24 illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art. 
In order to simplify the structures described in the above schemes, mutiple designations of a substituent (i.e. R2, R3, R8, etc.) have not always been included. However, it is understood that there may be several, independently selected substitutients around each of the rings described hereinabove, as seen in formulae A-D, hereinabove.
In a preferred embodiment of the instant invention the compounds of the invention are selective inhibitors of farnesyl-protein transferase. A compound is considered a selective inhibitor of farnesyl-protein transferase, for example, when its in vitro farnesyl-protein transferase inhibitory activity, as assessed by the assay described in Example 71, is at least 100 times greater than the in vitro activity of the same compound against geranylgeranyl-protein transferase-type I in the assay described in Example 72. Preferably, a selective compound exhibits at least 1000 times greater activity against one of the enzymatic activities when comparing geranylgeranyl-protein transferase-type I inhibition and farnesyl-protein transferase inhibition.
It is also preferred that the selective inhibitor of farnesyl-protein transferase is further characterized by:
a) an IC50 (a measure of in vitro inhibitory activity) for inhibition of the prenylation of newly synthesized K-Ras protein more than about 100-fold higher than the EC50 for the inhibition of the farnesylation of hDJ protein. When measuring such IC50s and EC50s the assays described in Example 76 may be utilized.
It is also preferred that the selective inhibitor of farnesyl-protein transferase is further characterized by:
b) an IC50 (a measurement of in vitro inhibitory activity) for inhibition of K4B-Ras dependent activation of MAP kinases in cells at least 100-fold greater than the EC50 for inhibition of the farnesylation of the protein hDJ in cells.
It is also preferred that the selective inhibitor of farnesyl-protein transferase is further characterized by:
c) an IC50 (a measurement of in vitro inhibitory activity) against H-Ras dependent activation of MAP kinases in cells at least 1000 fold lower than the inhibitory activity (IC50) against H-ras-CVLL (SEQ.ID.NO.: 1) dependent activation of MAP kinases in cells.
When measuring Ras dependent activation of MAP kinases in cells the assays described in Example 75 may be utilized.
In another preferred embodiment of the instant invention the compounds of the invention are dual inhibitors of farnesyl-protein transferase and geranylgeranyl-protein transferase type I. Such a dual inhibitor may be termed a Class II prenyl-protein transferase inhibitor and will exhibit certain characteristics when assessed in in vitro assays, which are dependent on the type of assay employed.
In a SEAP assay, such as described in Example 75, it is preferred that the dual inhibitor compound has an in vitro inhibitory activity (IC50) that is less than about 12 xcexcM against K4B-Ras dependent activation of MAP kinases in cells.
The Class II prenyl-protein transferase inhibitor may also be characterized by:
a) an IC50 (a measurement of in vitro inhibitory activity) for inhibiting K4B-Ras dependent activation of MAP kinases in cells between 0.1 and 100 times the IC50 for inhibiting the farnesylation of the protein hDJ in cells; and
b) an IC50 (a measurement of in vitro inhibitory activity) for inhibiting K4B-Ras dependent activation of MAP kinases in cells greater than 5-fold lower than the inhibitory activity (IC50) against expression of the SEAP protein in cells transfected with the pCMV-SEAP plasmid that constitutively expresses the SEAP protein.
The Class II prenyl-protein transferase inhibitor may also be characterized by:
a) an IC50 (a measurement of in vitro inhibitory activity) against H-Ras dependent activation of MAP kinases in cells greater than 2 fold lower but less than 20,000 fold lower than the inhibitory activity (IC50) against H-ras-CVLL (SEQ.ID.NO.: 1) dependent activation of MAP kinases in cells; and
b) an IC50 (a measurement of in vitro inhibitory activity) against H-ras-CVLL dependent activation of MAP kinases in cells greater than 5-fold lower than the inhibitory activity (IC50) against expression of the SEAP protein in cells transfected with the pCMV-SEAP plasmid that constitutively expresses the SEAP protein.
The Class II prenyl-protein transferase inhibitor may also be characterized by:
a) an IC50 (a measurement of in vitro inhibitory activity) against H-Ras dependent activation of MAP kinases in cells greater than 10-fold lower but less than 2,500 fold lower than the inhibitory activity (IC50) against H-ras-CVLL (SEQ.ID.NO.: 1) dependent activation of MAP kinases in cells; and
b) an IC50 (a measurement of in vitro inhibitory activity) against H-ras-CVLL dependent activation of MAP kinases in cells greater than 5 fold lower than the inhibitory activity (IC50) against expression of the SEAP protein in cells transfected with the pCMV-SEAP plasmid that constitutively expresses the SEAP protein.
A method for measuring the activity of the inhibitors of prenyl-protein transferase, as well as the instant combination compositions, utilized in the instant methods against Ras dependent activation of MAP kinases in cells is described in Example 75.
In yet another embodiment, a compound of the instant invention may be a more potent inhibitor of geranylgeranyl-protein transferase-type I than it is an inhibitor of farnesyl-protein transferase.
The instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors. Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e., neurofibromin (NF-1), neu, src, ab1, lck, fyn) or by other mechanisms.
The compounds of the instant invention inhibit farnesyl-protein transferase and the farnesylation of the oncogene protein Ras. The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575-4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of vision deficit related to retinal vascularization.
The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment. For example, the composition is useful in the treatment of neurofibromatosis, which is a benign proliferative disorder.
The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J. S. Glenn et al. Science, 256:1331-1333 (1992).
The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1:541-545(1995).
The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D. L. Schaffner et al. American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al. FASEB Journal, 2:A3160 (1988)).
The instant compounds may also be useful for the treatment of fungal infections.
The instant compounds may also be useful as inhibitors of proliferation of vascular smooth muscle cells and therefore useful in the prevention and therapy of arteriosclerosis and diabetic vascular pathologies.
The compounds of the instant invention may also be useful in the prevention and treatment of endometriosis, uterine fibroids, dysfunctional uterine bleeding and endometrial hyperplasia.
In such methods of prevention and treatment as described herein, the prenyl-protein transferase inhibitors of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, the prenyl-protein transferase inhibitor may be useful in further combination with drugs known to supress the activity of the ovaries and slow the growth of the endometrial tissue. Such drugs include but are not limited to oral contraceptives, progestins, danazol and GnRH (gonadotropin-releasing hormone) agonists.
Administration of the prenyl-protein transferase inhibitor may also be combined with surgical treatment of endometriosis (such as surgical removal of misplaced endometrial tissue) where appropriate.
The instant compounds may also be useful as inhibitors of corneal inflammation. These compounds may improve the treatment of corneal opacity which results from cauterization-induced corneal inflammation. The instant compounds may also be useful in reducing corneal edema and neovascularization. (K. Sonoda et al., Invest. Ophthalmol. Vis. Sci., 1998, vol. 39, p 2245-2251).
The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
Additionally, the compounds of the instant invention may be administered to a mammal in need thereof using a gel extrusion mechanism (GEM) device, such as that described in U.S. Ser. No. 60/144,643, filed on Jul. 20, 1999, which is hereby incorporated by reference.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water soluble taste masking material such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring agents, preservatives and antioxidants.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous solutions. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution.
The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.
The injectable solutions or microemulsions may be introduced into a patient""s blood-stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS(trademark) model 5400 intravenous pump.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compounds of Formula A may also be administered in the form of a suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula A are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
The compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, sex and response of the individual patient, as well as the severity of the patient""s symptoms.
In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
The compounds of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, the compounds of the instant invention may also be co-administered with other well known cancer therapeutic agents that are selected for their particular usefulness against the condition that is being treated. Included in such combinations of therapeutic agents are combinations of the instant farnesyl-protein transferase inhibitors and an antineoplastic agent. It is also understood that such a combination of antineoplastic agent and inhibitor of farnesyl-protein transferase may be used in conjunction with other methods of treating cancer and/or tumors, including radiation therapy and surgery. It is further understood that any of the therapeutic agents described herein may also be used in combination with a compound of the instant invention and an antineoplastic agent.
Examples of an antineoplastic agent include, in general, microtubule-stabilizing agents (such as paclitaxel (also known as Taxol(copyright)), docetaxel (also known as Taxotere(copyright)), epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B or their derivatives); microtubule-disruptor agents; alkylating agents, for example, nitrogen mustards, ethyleneimine compounds, alkyl sulfonates and other compounds with an alkylating action such as nitrosoureas, cisplatin, and dacarbazine; anti-metabolites, for example, folic acid, purine or pyrimidine antagonists; epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; mitotic inhibitors, for example, vinca alkaloids and derivatives of podophyllotoxin; cytotoxic antibiotics; hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors and antibodies (such as trastuzumab (Herceptin(trademark))).
Example classes of antineoplastic agents include, for example, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the epothilones, discodermolide, the pteridine family of drugs, diynenes and the podophyllotoxins. Particularly useful members of those classes include, for example, doxorubicin, canninomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like. Other useful antineoplastic agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), procarbazine, mitomycin, cytarabine, etoposide, methotrexate, bleomycin, chlorambucil, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins. Particular examples of antineoplastic, or chemotherapeutic, agents are described, for example, by D. J. Stewart in xe2x80x9cNausea and Vomiting: Recent Research and Clinical Advancesxe2x80x9d, Eds. J. Kucharczyk, et al., CRC Press Inc., Boca Raton, Fla., USA (1991), pages 177-203, especially page 188. See also, R. J. Gralla, et al., Cancer Treatment Reports, 68(1), 163-172 (1984).
The preferred class of antineoplastic agents is the taxanes and the preferred antineoplastic agent is paclitaxel.
A compound of the present invention may be employed in conjunction with antiemetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy. For the prevention or treatment of emesis a compound of the present invention may be used in conjunction with other anti-emetic agents, especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, or a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712. For the treatment or prevention of emesis, conjunctive therapy with a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is preferred.
Neurokinin-1 receptor antagonists of use in conjunction with the compounds of the present invention are fully described, for example, in U.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European Patent Publication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430 771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0 512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394, 0 585 913, 0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; PCT International Patent Publication Nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95120575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293 169, and 2 302 689. The preparation of such compounds is fully described in the aforementioned patents and publications.
A particularly preferred neurokinin-1 receptor antagonist for use in conjunction with the compounds of the present invention is 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Pat. No. 5,719,147.
For the treatment of cancer, it may be desirable to employ a compound of the present invention in conjunction with another pharmacologically active agent(s). A compound of the present invention and the other pharmacologically active agent(s) may be administered to a patient simultaneously, sequentially or in combination. For example, the present compound may employed directly in combination with the other active agent(s), or it may be administered prior, concurrent or subsequent to the administration of the other active agent(s). In general, the currently available dosage forms of the known therapeutic agents for use in such combinations will be suitable.
For example, a compound of the present invention may be presented together with another therapeutic agent in a combined preparation, such as with an antiemetic agent for simultaneous, separate, or sequential use in the relief of emesis associated with employing a compound of the present invention and radiation therapy. Such combined preparations may be, for example, in the form of a twin pack. A preferred combination comprises a compound of the present invention with antiemetic agents, as described above.
Radiation therapy, including x-rays or gamma rays which are delivered from either an externally applied beam or by implantation of tiny radioactive sources, may also be used in combination with the instant inhibitor of prenyl-protein transferase alone to treat cancer.
Additionally, compounds of the instant invention may also be useful as radiation sensitizers, as described in WO 97/38697, published on Oct. 23, 1997, and herein incorporated by reference.
The instant compounds may also be useful in combination with other inhibitors of parts of the signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Thus, the instant compounds may be utilized in combination with farnesyl pyrophosphate competitive inhibitors of the activity of farnesyl-protein transferase or in combination with a compound which has Raf antagonist activity. The instant compounds may also be co-administered with compounds that are selective inhibitors of geranylgeranyl protein transferase.
In particular, if the compound of the instant invention is a selective inhibitor of farnesyl-protein transferase, co-administration with a compound(s) that is a selective inhibitor of geranylgeranyl protein transferase may provide an improved therapeutic effect.
In particular, the compounds disclosed in the following patents and publications may be useful as farnesyl pyrophosphate-competitive inhibitor component of the instant composition: U.S. Ser. Nos. 08/254,228 and 08/435,047. Those patents and publications are incorporated herein by reference.
In practicing methods of this invention, which comprise administering, simultaneously or sequentially or in any order, two or more of a protein substrate-competitive inhibitor and a farnesyl pyrophosphate-competitive inhibitor, such administration can be orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration. It is preferred that such administration be orally. It is more preferred that such administration be orally and simultaneously. When the protein substrate-competitive inhibitor and farnesyl pyrophosphate-competitive inhibitor are administered sequentially, the administration of each can be by the same method or by different methods.
The instant compounds may also be useful in combination with an integrin antagonist for the treatment of cancer, as described in U.S. Ser. No. 09/055,487, filed Apr. 6, 1998, and WO 98/44797, published on Oct. 15, 1998, which are incorporated herein by reference.
As used herein the term an integrin antagonist refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to an integrin(s) that is involved in the regulation of angiogenisis, or in the growth and invasiveness of tumor cells. In particular, the term refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the xcex1vxcex23 integrin, which selectively antagonize, inhibit or counteract binding of a physiological ligand to the xcex1vxcex25 integrin, which antagonize, inhibit or counteract binding of a physiological ligand to both the xcex1vxcex23 integrin and the xcex1vxcex25 integrin, or which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells. The term also refers to antagonists of the xcex11xcex21, xcex12xcex21, xcex15xcex21, xcex16xcex21 and xcex16xcex24 integrins. The term also refers to antagonists of any combination of xcex1vxcex23 integrin, xcex1vxcex25 integrin, xcex11xcex21, xcex12xcex21, xcex15xcex21, xcex16xcex21 and xcex16xcex24 integrins. The instant compounds may also be useful with other agents that inhibit angiogenisis and thereby inhibit the growth and invasiveness of tumor cells, including, but not limited to angiostatin and endostatin.
The instant compounds may also be useful in combination with an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) for the treatment of cancer. Compounds which have inhibitory activity for HMG-CoA reductase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33. The terms xe2x80x9cHMG-CoA reductase inhibitorxe2x80x9d and xe2x80x9cinhibitor of HMG-CoA reductasexe2x80x9d have the same meaning when used herein.
Examples of HMG-CoA reductase inhibitors that may be used include but are not limited to lovastatin (MEVACOR(copyright); see U.S. Pat. Nos. 4,231,938; 4,294,926; 4,319,039), simvastatin (ZOCOR(copyright); see U.S. Pat. Nos. 4,444,784; 4,820,850; 4,916,239), pravastatin (PRAVACHOL(copyright); see U.S. Pat. Nos. 4,346,227; 4,537,859; 4,410,629; 5,030,447 and 5,180,589), fluvastatin (LESCOL(copyright); see U.S. Pat. Nos. 5,354,772; 4,911,165; 4,929,437; 5,189,164; 5,118,853; 5,290,946; 5,356,896), atorvastatin (LIPITOR(copyright); see U.S. Pat. Nos. 5,273,995; 4,681,893; 5,489,691; 5,342,952) and cerivastatin (also known as rivastatin and BAYCHOL(copyright); see U.S. Pat. No. 5,177,080). The structural formulas of these and additional HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, xe2x80x9cCholesterol Lowering Drugsxe2x80x9d, Chemistry and Industry, pp. 85-89 (Feb. 5, 1996) and U.S. Pat. Nos. 4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefor the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention. An illustration of the lactone portion and its corresponding open-acid form is shown below as structures I and II. 
In HMG-CoA reductase inhibitor""s where an open-acid form can exist, salt and ester forms may preferably be formed from the open-acid, and all such forms are included within the meaning of the term xe2x80x9cHMG-CoA reductase inhibitorxe2x80x9d as used herein. Preferably, the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin, and most preferably simvastatin. Herein, the term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d with respect to the HMG-CoA reductase inhibitor shall mean non-toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidine-1xe2x80x2-yl-methyl-benzimidazole, diethylamine, piperazine, and tris(hydroxymethyl)aminomethane. Further examples of salt forms of HMG-CoA reductase inhibitors may include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.
Ester derivatives of the described HMG-CoA reductase inhibitor compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
Similarly, the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-1, restenosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
If formulated as a fixed dose, such combination products employ the combinations of this invention within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range. Combinations of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a multiple combination formulation is inappropriate.
The instant compounds may also be useful in combination with prodrugs of antineoplastic agents. In particular, the instant compounds may be co-administered either concurrently or sequentially with a conjugate (termed a xe2x80x9cPSA conjugatexe2x80x9d) which comprises an oligopeptide, that is selectively cleaved by enzymatically active prostate specific antigen (PSA), and an antineoplastic agent. Such co-administration will be particularly useful in the treatment of prostate cancer or other cancers which are characterized by the presence of enzymatically active PSA in the immediate surrounding cancer cells, which is secreted by the cancer cells.
Compounds which are PSA conjugates and are therefore useful in such a co-administration, and methods of synthesis thereof, can be found in the following patents, pending patent applications and publications which are herein incorporated by reference:
U.S. Pat. No. 5,599,686, granted on Feb. 4, 1997;
WO 96/00503 (Jan. 11, 1996); U.S. Ser. No. 08/404,833, filed on Mar. 15, 1995; U.S. Ser. No. 08/468,161, filed on Jun. 6, 1995;
U.S. Pat. No. 5,866,679, granted on Feb. 2, 1999;
WO 98/10651 (Mar. 19, 1998); U.S. Ser. No. 08/926,412, filed on Sep. 9, 1997;
WO 98/18493 (May 7, 1998); U.S. Ser. No. 08/950,805, filed on Oct. 14, 1997;
WO 99/02175 (Jan. 21, 1999); U.S. Ser. No. 09/112,656, filed on Jul. 9, 1998; and
WO 99/28345 (Jun. 10, 1999); U.S. Ser. No. 09/193,365, filed on Nov. 17, 1998.
Compounds which are described as prodrugs wherein the active therapeutic agent is released by the action of enzymatically active PSA and therefore may be useful in such a co-administration, and methods of synthesis thereof, can be found in the following patents, pending patent applications and publications, which are herein incorporated by reference: WO 98/52966 (Nov. 26, 1998).
All patents, publications and pending patent applications identified are herein incorporated by reference.
The compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of farnesyl-protein transferase (FPTase) in a composition. Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of the assay mixtures may be determined by well known immuno-logical, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain farnesyl-protein transferase and quantitating the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention. The concentration of a sufficiently potent inhibitor (i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel) required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample.